The long-term goal is to improve diagnostic decision making during coronary intervention. The fundamental gap of knowledge in cardiovascular diagnostics is that a single endpoint that combines functional (pressure drop-flow hemodynamics) and anatomic measurements to assess epicardial stenoses with or without microvascular impairment does not exist. Thus, there is a need for a combined functional and anatomical quantification upon which a decision for angio- plasty or bypass surgery can be made more accurately. The objective is to accurately delineate microvascular impairment from different degrees of epicardial stenoses. The central hypothesis is that the functional endpoint pressure drop coefficient (CDPe) and the lesion flow coefficient (LFC), an additional and more comprehensive diagnostic endpoint that combines functional (CDPe) and anatomical evidence, will better assess for critical stenosis than empirical methods used for clinical assessment of diseased coronary arteries. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) To assess the efficacy of CDPe, the functional endpoint, in distinguishing concomitant epicardial and microvascular dysfunc- tion independently. The working hypothesis is that, in human ischemic heart disease, the extent of diagnostic abnormalities identified by cut-off values of CDPe correlate well with those that can be detected from established invasive modalities such as IVUS, FFR, and CFR and with non- invasive modalities, such as single photon emission computed tomography (SPECT) and a rela- tively newer technique of positron emission tomography (PET);2) To evaluate the effectiveness of LFC that combines functional (CDPe) and anatomical endpoints in distinguishing concomi- tant epicardial artery and microvascular diseases independently. The working hypothesis is that the extent of diagnostic abnormalities identified by cut-off values of LFC correlate well with those that can be detected from known modalities such as IVUS, FFR, CFR, SPECT and PET;3) To establish the difference in CDPe and LFC values between the coronary arteries of younger and advanced age hearts showing variable arterial wall compliance. The working hypothesis here is that the arteries of older hearts show the effect of lower wall compliance due to the change in non-linear wall-elasticity as compared to the arteries of younger hearts, allowing us to delineate the arterial compliance effect of our published mathematical formulation of CDPe and LFC. This study incorporates an innovative approach of combining functional and anatomic endpoints for better diagnosis that are based on fundamental fluid dynamic principles. This research is sig- nificant because it is expected to remove the 'guesswork'from clinical decision-making process. PUBLIC HEALTH RELEVANCE: Results from the proposed research on guide-wire diagnostics are expected to have an important positive impact on significant portion of the aging VA population by providing an improved diagnostic capability and by reducing the variability of therapeutic outcome in persons with coronary cardiovascular disease. More than 100,000 patients per year are recruited for cardiovascular assessment as per the VA Registry. These proposed diagnostic parameters pressure drop coefficient and lesion flow coefficient have broad relevance to the VA mission for improving cardiovascular health and have the potential to make a real, not theoretical, paradigm shift in clinical decision making related to cardiovascular intervention. The proposed research on guide-wire diagnostics is an important but under-investigated area of cardiovascular disease assessment. The expected outcome of this project is that the diagnostic parameters will differentiate in human hearts diverse extents of microvascular impairment from epicardial arterial stenosis.